Generating diverse progenies from a limited number of progenitor cells is a significant challenge for multicellular organisms. The progenitor cells need to continuously renew themselves while generating new cell types; this process requires asymmetric cell divisions (ACD), a hallmark of stem cells. The key process during ACD is the cellular polarization of progenitor cells, which is initiated by either extrinsic or intrinsic cuesand eventually determines the adoption of differential cell fates in the two daughter cells. The long-term goal of our research is to elucidate the design principles and paradigms that govern the orchestrated events during cellular polarization and fate determination in ACD. The formation and patterning of stomata require precisely regulated ACDs. The Arabidopsis stomata system provides an excellent platform to study the mechanisms for ACD in plants, because these divisions are stereotypic and highly predictable, and the leaf epidermis exposed in air is readily accessible to genetic characterization and cellular examination. Benefited from the advantages of the stomatal system, the novel protein, BASL (Break Asymmetry of the Stomatal Lineages), is the first intrinsic polarity protein identified in plants that controls ACD by its highly polarized distribution at the plasma membrane. However, how BASL polarity is formed and how it regulates stomatal ACD remains elusive. The central hypothesis in this application is that a new feedback regulation between the polarity protein BASL and a conserved MAPK pathway plays an important role in cell polarity establishment and asymmetric cell fate determination. Three specific aims in this proposal are: 1) to elucidate the molecular mechanisms by which BASL is polarized from the nucleus to the cell cortex, 2) to investigate the inter-dependency between BASL and the MAPK pathway and the machineries that control BASL-based polarity at the plasma membrane, and 3) to establish a new paradigm for how polarity proteins coordinate daughter cell fates in plant ACD. Besides this core theme, the proposed genome-wide investigation of BASL physical partners and novel genetic networks promises to provide the first glimpse of the systematic control of intrinsic cell polarity establishment during ACD in plants. The molecular mechanisms under investigation involve protein subcellular polarization, polarity protein- driven cell fate specification, and MAPK functions in balancing cell division and differentiation, which are all clearly linked to the studies of human stem cell activity and homeostasis.